1. Field of the Invention
The present invention relates to pharmaceutical compositions and, more particularly, but not by way of limitation, to novel compositions and methods for inhibition of pathophysiologic effects of excessive amounts of TNF-.alpha. in the blood, tissues, or organs of mammals including humans.
2. Background Art
Current evidence indicates that seemingly diverse immune-mediated diseases involve similar pathogenic mechanisms, and a growing number of key effector molecules known as cytokines. A biochemical cascade of pathophysiologic events is triggered by excessive tissue or blood concentrations of TNF-.alpha. released or synthesized following cellular, tissue, or organ injury. TNF-.alpha. plays a prominent role in immune and host defense response. There is strong evidence that abnormally high production and release from cells of TNF-.alpha. contributes to disease initiation and progression in rheumatoid arthritis, systemic inflammatory syndromes, diabetes, multiple sclerosis, and many other immune-mediated disorders (L. Propert, J. Leukocyte Biol., 59:518-525, 1996).
In every one of these conditions, the initiating and sustaining pathophysiologic action is directly a result of an immediate local release and synthesis of massive amounts of TNF-.alpha. from several types of cells at or adjacent to the injury site. The locally released TNF-.alpha. is followed by additional synthesis and release of TNF-.alpha. by invading macrophages drawn to the injury site by a cascade of chemotactic cytokines released locally from cells in response to the greatly elevated TNF-.alpha. concentrations.
TNF-.alpha. is a 17 kDa, multi-functional peptide produced by a wide variety of cells during host responses to tissue or organ injury including microbial infections and neoplastic diseases. Activated macrophages are a major cellular source for TNF-.alpha., although other cell types such as T-cells, mast cells, neutrophils, endothelial cells, microglia, and astrocytes can be stimulated to secrete TNF-.alpha.. TNF-.alpha. also plays an important role in the initiation of inflammation and the pathophysiologic consequences that result from this process.
There are several disease states in which excessive or unregulated TNF-alpha production by monocytes, macrophages or related cells are implicated in exacerbating and/or causing the disease. These include endotoxemia (sepsis), toxic shock syndrome (Tracey et al., Nature, 330:662-64, 1987; Basger et al., Circ. Shock. 27:51-61, 1989, and Hinshaw et al., 30:279-292, 1990); cachexia (Dezube et al., Lancet, 335 8690!:662, 1990); Adult Respiratory Distress Syndrome (ARDS) where TNF-.alpha. concentrations in excess of 12,000 pg per ml have been detected in pulmonary aspirates from ARDS patients (Millar et al., Lancet, 8665! 2, 712-714. Systemic infusion of recombinant TNF-alpha resulted in changes typically seen in ARDS (Ferrai-Baliviera et al., Arch. Surgery, 124:1400-1405, 1989.) TNF-.alpha. is widely expressed in monocytes, macrophages, lymphocytes, natural killer cells, endothelial cells, mast cells, neutrophils and eosinophils, glial cells and astrocytes, smooth muscle cells and certain tumor cells. TNF-.alpha. can be produced mainly by lymphocytes, astrocytes, lymphokine-activated killer cells and myeloma cells. Overproduction of TNF-.alpha. and/or .beta. is closely linked to development of many diseases, including septic shock, adult respiratory distress syndrome, rheumatoid arthritis, selective autoimmune disorders, graft-host disease following bone marrow transplantation and cachexia. Other diseases associated with excessive TNF- production include: hemorrhagic shock, asthma and post-renal dialysis syndrome. The multiplicity of actions of TNF-.alpha. and -.beta. can be ascribed to the facts that TNF-.alpha. and -62 actions result in activation of multiple signal transduction pathways, kinases, transcription factors, as well as an unusually large array of cellular genes. (Walajtys-Rode, Elizbieta, Kosmos (Warsaw), 44, 451-464, 1995, C.A. 124:199735a, 1995).
TNF-.alpha. exhibits a plethora of other functions such as induction of IL1, stimulation of neutrophil degranulation, and enhancement of phagocytosis. Endotoxin from gram negative bacteria has been used to induce TNF-.alpha. both in vivo and in vitro. In addition to endotoxin, certain micro-organisms as well as other substances, such as IL1, are capable of inducing secretion of TNF-.alpha. from stimulated peritoneal macrophages. (H. J. Wanebo, "Tumor Necrosis Factors," Seminars in Surgical Oncology, 1989, 5:402-413.)
Thus, TNF-.alpha. is a potent immunomediator and proinflammatory cytokine that has been implicated in the pathogenesis of a large number of human diseases. The location of its gene within the major histocompatability complex and biological activities have raised the possibility that polymorphism within this locus may contribute to the genetic association of this region of the genome with a wide range of autoimmune and infectious diseases.
TNF-.alpha. inhibitors can be useful in the therapeutic or prophylactic treatment of a variety of allergic and traumatic disorders including asthma, chronic bronchitis, many skin disorders (including atopic dermatitis and urticaria), allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, reperfusion injury of the myocardium or brain, cystic fibrosis, chronic glomerulonephritis, and adult respiratory distress syndrome (ARDS). The principal cytokine that mediates the complex processes triggered by injury to a cell or tissue is TNF-.alpha. which elicits complex biological responses from virtually every type of cell that it binds. (Jour. Cardiovas. Pharm., 25(S1-S8, 1995).
TNF-.alpha. antagonists can be very effective in the treatment of disorders which follow cellular, tissue or organ injury, and may be as effective, or even more potent, than corticosteroids or immunosuppressants without producing the side effects common to these agents.